Post Conference HCV Update 49 th Annual Meeting of the European Association for the Study of the...

Post Conference HCV Update

49th Annual Meeting of the European Association for the Study of the Liver

Supported by an independent educational grant from Gilead Sciences Medical Affairs

Co-provided for CME/CE credit by theUniversity of Nebraska Medical Center

and Practice Point Communications

Simply Speaking® Hepatitis “Post Conference HCV Update: 49th Annual Meeting of the European Association for the Study of the Liver” isCopyrighted 2014 by Practice Point Communications, unless otherwise noted. All rights reserved.

2

Content Development & Training Faculty

Tram Tran, MDMedical Director, Liver Transplantation

Cedars-Sinai Medical CenterHepatology and Liver TransplantAssociate Professor of Medicine

UCLA School of MedicineLos Angeles, CA

● Disclosures- Grants/Research Support: Bristol-Myers Squibb

- Consultant: Bristol-Myers Squibb, Enanta, Gilead Sciences

- Speakers’ Bureau: None

- Stock Shareholder: None

- Other Financial or Material Support: None

3

Learning Objectives(CME/CNE/CPE)

● Upon completion of this educational activity, participants should be able to:- Screen for hepatitis C virus (HCV) infection according to the

recommendations from the American Association for the Study of Liver Diseases (AASLD) and the Centers for Disease Control and Prevention (CDC)

- Appropriately select antiviral HCV treatment strategies according to the recommendations from the AASLD/IDSA guidelines

- Manage safety and tolerability problems with antiviral HCV agents, including side effect, drug-drug interactions, and resistance

- Evaluate new agents being investigated for HCV therapy to optimize information-based decision making about therapy

4

Program Overview

● HCV epidemiology and public health considerations

● Interferon-free regimens for HCV

- Treatment-naïve patients

- Treatment-experienced patients

- Retreatment for prior DAA failures

- Difficult-to-cure and liver transplant patients

- HCV/HIV coinfection

5

Global Burden of Disease Study 2010:Causes of Death From Chronic Liver Disease

● In 2010, HIV-related mortality in the EU/EFTA countries never reached those of HCV or HBV

● HCV is the predominant cause of death due to blood-borne viruses in the EU/EFTA

- Approximately 10 times to that of HIV/AIDS

- Greater than HBV and HIV combined

● Majority of HCV-related mortality due to cirrhosis

Cowie BC, et al. J Hepatol. 2014;60(suppl 1):S35-S36. Abstract O86.

Dea

ths

(nu

mb

er)

EU/EFTA (2010)

HCV HBV HIV

2010 Global deaths: HIV (1.47 million), HCV and HBV (1.29 million).

6

Impact of Comorbid Conditions on HCV Treatment Decisions (2002-2012)

● Retrospective cohort study (Kaiser Permanente Southern California) (n=32,283 HCV patients with prescription benefits)

- Received HCV therapy (17%)

• PegIFN + RBV + telaprevir or boceprevir

● Comorbid conditions (relative or absolute contraindications to IFN-based therapy): 50%

- 15% of these patients were treated

● Factors significantly associated with receiving therapy (P<0.01)

- Younger age (<45 versus >65 years and 45-65 versus >65 years), male gender, presence of cirrhosis, HIV coinfection, NAFLD/NASH, depression, prior liver transplant

Nyberg LM, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O67.

AdjustedOdd Ratio

Anemia 0.32*

Autoimmune disorder 0.78†

Renal dysfunction 0.66†

Cardiovascular disease 0.60*

Psychosis/bipolar 0.68†

Severe lung disease 0.56*

Substance abuse 0.54*

MELD >12 0.39*

Factors Associated With Not Achieving HCV Therapy

*P<0.0001 and †P<0.01.

7

Program Overview


● Interferon-free regimens for HCV

- Treatment-naïve patients





8

Sofosbuvir-Based Regimens in Treatment-Naïve Patients

● Sofosbuvir/ledipasvir + RBV

- ION-1 (12 versus 24 weeks)

- ION-3 (8 versus 12 weeks)

● Sofosbuvir long-term, follow-up registries

● Sofosbuvir + GS-5816

9

ION-1: Sofosbuvir/Ledipasvir + RBV in Treatment-Naïve, HCV Genotype 1

Afdhal N, et al. N Engl J Med. 2014;April 11. [Epub ahead of print].

Sofosbuvir/Ledipasvir qd(n=214)

Phase 3Open-label, randomizedGenotype 1Treatment-naïveTarget 20% cirrhoticsNo upper age or BMI criteriaPlatelets >50K/mm3

No neutrophil minimum

Week 0 12 24

Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor)/ledipasvir 90 mg (NS5A inhibitor) + RBV (1000-1200 mg).Primary endpoint: SVR12.Baseline demographics and disease characteristics: Male: 55% to 64%. Age: 52-53 years. Black: 11%-15%. Genotype 1a: 66%-68%. IL28B non-CC: 64% to 76%. HCV RNA (log10 IU/mL): 6.3-6.4. HCV RNA >800K IU/mL: 77%-80%.

Sofosbuvir/Ledipasvir qd+ RBV (n=217)



10

ION-1: SVR12 Rates With Sofosbuvir/Ledipasvir+ RBV in Treatment-Naïve, HCV Genotype 1

Overall No cirrhosis Cirrhosis

SV

R12

(%

)

99% 97%100% 100% 100%100%

12-Week Arm

No RBV(n=214/179/33)

RBV(n=217/178/33)

Sofosbuvir/Ledipasvir qd

Overall No cirrhosis Cirrhosis

SV

R12

(%

)

99% 97%99% 100% 100%100%

24-Week Arm

No RBV(n=217/182/32)

RBV(n=217/179/36)



11

ION-1: Non-SVR12 Achievers, Resistance, and Safety Results

● Non-SVR12 achievers

- Virologic breakthrough (n=1 due to noncompliance)

- Relapse

• 12-week arm (n=1)


● No S282T detected at baseline or at time of virologic failure

● Higher incidence of adverse events and laboratory abnormalities in the RBV-containing arms

- Fatigue, insomnia, asthenia, irritability, rash, cough, pruritus, and anemia

● Adverse events rates were generally higher in the 24-week arm

NoRBV

(n=214)RBV

(n=217)

NoRBV

(n=217)

NoRBV

(n=217)

Adverse events (%) Grade 3/4 Discontinuations

20

60

102

63

Death (number) 0 0 0 0

Laboratory abnormalities (%) Grade 3/4 Hemoglobin <10 g/dL <8.5 g/dL

5

00

10

9<1

10

00

12

70

Safety Summary for Sofosbuvir/Ledipasvir qd

12 Weeks 24 Weeks


12

ION-3: Sofosbuvir/Ledipasvir + RBV in Treatment-Naïve, HCV Genotype 1

Kowdley KV, et al. N Engl J Med. 2014;April 10. [Epub ahead of print].



Phase 3Open-label, non-inferiorityGenotype 1Treatment-naïveNon-cirrhoticNo upper age or BMI criteriaOpiate substitution allowed

Week 0 8 12 24

Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor)/ledipasvir 90 mg (NS5A inhibitor) + RBV (1000-1200 mg).Primary endpoint: SVR12.Baseline demographics and disease characteristics: Male: 54% to 61%. Age: 51-53 years. Black: 17%-21%. Genotype 1a: 80% IL28B non-CC: 72% to 74%. HCV RNA (log10 IU/mL): 6.4-6.5. HCV RNA >800K IU/mL: 79%-84%.


13

ION-3: SVR12 Rates With Sofosbuvir/Ledipasvir+ RBV in Treatment-Naïve, HCV Genotype 1

SV

R12

(%

)

94% 95%

No RBV(n=215)

Sofosbuvir/ledipasvir qd

8 weeks 8 weeks, with RBV 12 weeks

RBV(n=216)

8 Weeks

No RBV(n=216)

93%

*Met non-inferiority criteria (12% margin) for all between group comparisons.

12 Weeks

Overall SVR12*


SV

R12

(%

)

93% 95%

Genotype 1a(n=171/172/172)

Genotype 1b(n=43/44/44)

92%98% 98%96%

SVR12 by HCV Subtype


14

ION-3: SVR12 Rates by Prespecified Subgroups (Treatment-Naïve)

SV

R12

(%

)

97% 96%

<800K(n=34/45/44)

Sofosbuvir/ledipasvir qd

8 weeks 8 weeks, with RBV 12 weeks

96%93% 95%92%

96% 96%95% 93% 95%92% 92%

95%91%

98% 96%96%91%

95%89%

95% 95%94%

>800K(n=181/171/172)

CC(n=56/60/56)

Non-CC(n=159/156/160)

Male(n=130/117/128)

Female(n=85/99/8)

Black(n=45/36/42)

Non-Black(n=170/180/173)

Baseline HCV RNA(IU/mL)

IL28BGenotype

Gender Race


15

ION-3: Non-SVR12 Achieversand Safety Results


- No virologic breakthroughs

- Relapse


• 8-week (RBV) arm (n=9)



- Fatigue, headache, nausea, insomnia, irritability, rash, pruritus, and anemia

NoRBV

(n=216)RBV

(n=216)

NoRBV

(n=216)


<10

4<1

3<1

Death (number) 0 0 0


3

00

8

50

7

<10


8 Weeks12

Weeks


16

Long-Term Follow-Up of Sofosbuvir-Treated Patients in Phase 3 Trials

● Long-term follow-up registries (sofosbuvir phase 3 studies)

- SVR registry (achieved SVR24)

- Sequence registry (SVR24 non-achievers)

● SVR24 was durable in all patients in SVR registry after a median follow-up of 170 days

● Grade 3/4 laboratory abnormalities

- Higher incidence among Sequence registry (SVR24 non-achievers)

Cheng W, et al. J Hepatol. 2014;60(suppl 1):S449. Abstract P1112.

SVR24Registry(n=480)

SequenceRegistry(n=116)

Baseline Age (years) Male (%) Black (%) IL28B non-CC (%) Cirrhosis (%) Genotype 1/2/3/4-6 (%)

53598

3517

40/31/25/4

54825

3336

21/7/72/<1

Follow-up (days) 170 204

Outcomes (%) SVR durability Grade 3/4 ALT/AST Grade 3 Albumin Bilirubin Platelets

1000/0

<100

N/A8/8

120

Baseline and Outcomes Data

17

Sofosbuvir + GS-5816 inTreatment-Naïve, HCV Genotypes 1-6

Everson GT, et al. J Hepatol. 2014;60(suppl 1):S46. Abstract O111.

Sofosbuvir + GS-5816 25 mg qd

Phase 2Open-labelTreatment-naïve Genotypes: 1 (n=55) 3 (n=54) 2-6 (n=45)Non-cirrhotic Week 0 12 24

Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor) + GS-5816 (NS5A inhibitor).Primary endpoint: SVR12.Baseline demographics and disease characteristics: Male: 64%. Age: 50-51 years. Black: 3%-13%. Genotype 1a: 29%. IL28B non-CC: 32%-40%. HCV RNA (log10 IU/mL): 6.4.

Sofosbuvir + GS-5816 100 mg qd

18

Treatment Outcomes With Sofosbuvir +GS-5816 in Treatment-Naïve, HCV Genotypes 1-6

● SVR12 rates >90% in genotypes 1-6

- Presence of pretreatment NS5A variants was not predictive of failure to achieve SVR12


- Relapse: genotype 1 (n=1), genotype 3 (n=2)

• 2/3 relapsers received GS-5816 25 mg

● Sofosbuvir + GS-5816 was well tolerated

- No discontinuations due to adverse events

- No hemoglobin <10 g/dL

- Grade 3/4

• Adverse events (1.3%)

• Laboratory abnormalities (4.1%)

Pat

ien

ts (

%)

100% 100% 100%

SVR12 Rates

1(n=27/28)

Sofosbuvir + GS-5816 25 mg qdSofosbuvir + GS-5816 100 mg qd

Genotype

Everson GT, et al. J Hepatol. 2014;60(suppl 1):S46. Abstract O111.

100% 100%96%

91% 93%

86%

2(n=11/10)

3(n=27/27)

4(n=7/7)

5(n=1)

6(n=4/5)

19

ABT-450/r/Ombitasvir + Dasabuvir + RBV in Treatment-Naïve Patients

● SAPPHIRE-I (genotype 1)

● PEARL-III (genotype 1b)

20

SAPPHIRE-I: ABT-450/r/Ombitasvir + Dasabuvir + RBV in Treatment-Naïve, HCV Genotype 1

Feld JJ, et al. N Engl J Med. 2014;370:1594-1603.

3D + RBV(n=473)

Phase 3Double-blindGenotype 1Treatment-naïveNon-cirrhotic18 to 70 years of age

Week 0 12 24

3D: ABT-450 (NS3/4A inhibitor)/r/ombitasvir (NS5A inhibitor) 150/100/25 mg qd; dasabuvir (non-nucleoside NS5B polymerase inhibitor) 250 mg bid. RBV (1000-1200 mg).Primary endpoint: SVR12 versus historical control SVR rate: 78% (telaprevir + pegIFN + RBV).Baseline demographics and disease characteristics: Male: 46% to 57%. Age: 52 years. Black: 5%-6%. Genotype 1a: 67%-68%. IL28B non-CC: 68%-70%. HCV RNA (log10 IU/mL): 6.5-6.6. Fibrosis stage F0-F1: 77%

Placebo(n=158)

3D + RBV

21

SAPPHIRE-I: SVR12 Rates With 3D + RBVin Treatment-Naïve, HCV Genotype 1

● Non-inferiority and superiority criteria met for overall SVR12 and superiority criteria met for SVR rate for genotype 1a and 1b

● SVR12 rates were similar across patient subgroups

- Baseline HCV RNA, IL28B, BMI, fibrosis stage, gender, race

● SVR12 non-achievers

- Virologic breakthrough (n=1)

- Relapse (n=7)

• Genotype 1a

- All had >1 RAV at time of virologic failure

*

SV

R12

(%

)

96% 98%

Overall(n=473)

1a(n=322)

HCV Subtype

1b(n=151)

95%

SVR12Non-inferioritythreshold

Superioritythreshold


22

SAPPHIRE-I: Safety of 3D + RBVin Treatment-Naïve, HCV Genotype 1

● Most common adverse events associated with 3D + RBV versus placebo (P<0.05)

- Nausea, pruritus, insomnia, diarrhea, asthenia

● Serious adverse events possibly related to 3D + RBV (n=2)

- Patient 1: acute respiratory failure and hypoxia

- Patient 2: abdominal pain, sinus tachycardia, diarrhea, chiles, vomiting, nausea, and ventricular extrasystoles

● RBV dose modification due to adverse events (5.5%)

3D + RBV(n=473)


2.10.6

Death (number) 0

Laboratory abnormalities (%) ALT >5x ULN AST >5x ULN Alkaline phosphatase >5x ULN Total bilirubin >3x ULN Hemoglobin <10-8.0 g/dL <8.0 g/dL

0.90.60

2.8

5.80

Safety Summary


23

PEARL-III: ABT-450/r/Ombitasvir + Dasabuvir + RBV in Treatment-Naïve, HCV Genotype 1b

Ferenci P, et al. N Engl J Med. 2014;May 4. [Epub ahead of print].

3D + RBV(n=210)

Phase 3Double-blindGenotype 1bTreatment-naïveNon-cirrhotic18 to 70 years of ageBMI >18-<38 kg/m2

HCV RNA >10K IU/mLWeek 0 12 24

3D: ABT-450 (NS3/4A inhibitor)/r/ombitasvir (NS5A inhibitor) 150/100/25 mg qd; dasabuvir (non-nucleoside NS5B polymerase inhibitor) 250 mg bid. RBV (1000-1200 mg).Primary endpoint: SVR12 versus historical control SVR rate: 73% (telaprevir + pegIFN + RBV).Baseline demographics and disease characteristics: Male: 41% to 51%. Age: 48-49 years. Black: 5%. IL28B non-CC: 79%. HCV RNA (log10 IU/mL): 6.3. HCV RNA >800K IU/mL: 71%-76%. Fibrosis stage F0-F1: 68%-71%.

3D + Placebo(n=209)

24

PEARL-III: SVR12 Rates With 3D + RBVin Treatment-Naïve, HCV Genotype 1b

● Non-inferiority and superiority criteria met versus historical control

● Non-inferiority criteria (10.5% margin) met for 3D + RBV versus 3D without RBV

● SVR12 rates in both arms were similar across patient subgroups

- Baseline HCV RNA, IL28B, fibrosis stage, gender, race



• Emergent NS5A Y93H at failure

*

SV

R12

(%

)

99%

3D + RBV(n=210)

3D(n=209)

99%

SVR12

Non-inferiority (73%)

Superiority (84%)


25

PEARL-III: Safety of 3D + RBVin Treatment-Naïve, HCV Genotype 1b

● Higher incidence of adverse events and laboratory abnormalities in the RBV-containing arm (P<0.05)

- Pruritus (12%), nausea (11%), asthenia (11%), anemia (9%)

● Serious adverse events possibly related to 3D (n=1)

- Arthritis of hands and feet (ANA and RF positive)

● RBV dose modification due to adverse events (9%)

- All patients achieved SVR12

3D + RBV

(n=210)3D

(n=209)


30

20

Death (number) 0 0

Laboratory abnormalities (%) ALT >5x ULN Total bilirubin >3x ULN Hemoglobin <10 g/dL (%)

1.05.79.0

00.50

Safety Summary


26

Daclatasvir + Asunaprevir in Patients With Varying Previous Treatment Exposures

● HALLMARK-DUAL (genotype 1b)

27

HALLMARK-DUAL Study: Daclatasvir + Asunaprevir in HCV Genotype 1b

Manns M, et al. J Hepatol. 2014;60(suppl 1):S524-S525. Abstract O166.Kao J-H, et al. J Hepatol. 2014;60(suppl 1):S527-S528. Abstract P1300.

Daclatasvir 60 mg (NS5A inhibitor; asunaprevir 100 mg (NS3 inhibitor).Primary endpoint: SVR12.Baseline characteristics: Age: 54-60 years; male: 42%-54%; black: 4%-7%. HCV RNA >800K IU/mL: 74%-87%. Cirrhosis: 16%-47%. IL28B non-CC: 61%-84%.

Daclatasvir qd + Asunaprevir bidTreatment-naïve (n=203)

Phase 3Genotype 1bCirrhotics allowedNon-cirrhotic18 to 70 years of age

Week 0 12 24

PlaceboTreatment-Naïve (n=158)

Daclatasvir qd + Asunaprevir bidPrior PR Partial/Null Responders (n=205)

Daclatasvir qd + Asunaprevir bidPR Ineligible/Intolerant (n=235)

28

HALLMARK-DUAL Study: Daclatasvir + Asunaprevir in HCV Genotype 1b

● SVR12 rates were similar

- Non-cirrhotic (85%) and cirrhotic (84%)

- Age, gender, race, IL28B genotype

● SVR12 rates were lower with baseline thrombocytopenia (<90 versus >90 x 109 cells/L)

- Overall: 71% versus 86%

- Advanced fibrosis/cirrhosis: 69% versus 78%

● Non-SVR12 achievers (3 treatment arms)

- Breakthroughs (4%, 13%, 9%)

- Relapse (3%, 4%, 6%)

- All had detectable RAVs at time of virologic failure

● Discontinuations due to adverse events: 1.5%

● Most common adverse events

- Headache, fatigue, diarrhea, nausea, asthenia

Manns M, et al. J Hepatol. 2014;60(suppl 1):S524-S525. Abstract O166.Kao J-H, et al. J Hepatol. 2014;60(suppl 1):S527-S528. Abstract P1300.

SV

R12

(%

)

90%

82%

Treatment-Naïve(n=203)

Prior PRPartial/NullResponder

(n=205)

PRIneligible/Intolerant

(n=235)

82%

SVR12

29

MK-5172 + MK-8742 + RBV inTreatment-Naïve Patients

● C-WORTHY (non-cirrhotic, genotype 1)

30

C-WORTHY Trial: MK-5172 + MK-8742+ RBV in Treatment-Naïve Patients

● Phase 2b study

- Non-cirrhotic, genotype 1

● MK-5172 + MK-8742 treatment arms

- Part A (12-week regimens)

• 100/20 mg + RBV (n=25)

• 100/50 mg + RBV (n=27)

• 100/50 mg (genotype 1b) (n=13)

- Part B (100/50 mg)

• 8 weeks (genotype 1a) (n=30)

• 12 weeks (n=33)

• 12 weeks (genotype 1a (n=31)

● Safety

- No deaths, discontinuations due to adverse events, grade 3/4 laboratory abnormalities

- Most common adverse events: fatigue, headache, nausea, diarrhea, insomnia

NoRBV(n=30)

WithRBV(n=85)

NoRBV(n=44)

SVR4-24* (%) Overall Genotype 1a (n=30/52/30)

Genotype 1b (n=0/33/14)

8383--

949494

9897

100

No SVR (%) Breakthrough Relapse Non-virologic

0170

114

020

Preliminary Outcomes:MK-5172 + MK-8742

8Weeks

12Weeks

*Part A: 12-week arms (100% completed SVR24); Part B:8 week arm (93% completed SVR8), 12-week arms (100% completed SVR8).

Hezode C, et al. J Hepatol. 2014;60(suppl 1):S5. Abstract O10.

31

Program Overview


● Interferon-free regimens for HCV- Treatment-naïve patients





32

Sofosbuvir-Based Studies in Treatment-Experienced Patients

● Sofosbuvir/ledipasvir

- ION-2: previous PR and DAA + PR failures

● Sofosbuvir + simeprevir

- COSMOS: previous PR failures

33

ION-2: Sofosbuvir/Ledipasvir + RBV in Treatment-Experienced, HCV Genotype 1


Phase 3Open-label, randomizedGenotype 1Treatment-experiencedTarget 20% cirrhoticsNo upper age or BMI criteriaPlatelets >50K/mm3

No neutrophil minimum

Week 0 12 24

Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor)/ledipasvir 90 mg (NS5A inhibitor) + RBV (1000-1200 mg).Primary endpoint: SVR12.Baseline demographics and disease characteristics: Male: 61% to 68%; age: 55-57 years; black: 14%-22%. Genotype 1a: 78%-79%. IL28B non-CC: 84% to 91%. Cirrhosis: 20%. HCV RNA (log10 IU/mL): 6.4-6.5. HCV RNA >800K IU/mL: 85%-95%. Prior non-responders: 41%-46%. Prior PI failures: 46%-61%.




Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.

34

ION-2: SVR12 Rates With Sofosbuvir/Ledipasvir+ RBV in Treatment-Experience, HCV Genotype 1

Overall Failed PR Failed PI + PR

SV

R12

(%

)

94% 96%93% 96% 97%94%

12-Week Arm

No RBV(n=109/43/47)

RBV(n=111/66/64)


SV

R12

(%

)

99% 98%100% 99% 100%98%

24-Week Arm

No RBV(n=109/58/59)

RBV(n=111/50/51)


PR: pegIFN + RBV.

Overall Failed PR Failed PI + PR


35

ION-2: SVR12 Rates by Presence of Cirrhosis With Sofosbuvir/Ledipasvir + RBV

No cirrhosis Cirrhosis

SV

R12

(%

)

95%86%

100%

82%

12-Week Arm

No RBV(n=87/22)

RBV(n=89/22)


SV

R12

(%

)

99% 100% 99% 100%

24-Week Arm

No RBV(n=87/22)

RBV(n=89/22)


PR: pegIFN + RBV.

No cirrhosis Cirrhosis


36

ION-2: Non-SVR12 Achievers, Resistance, and Safety Results


- Virologic breakthrough (n=1 due to noncompliance)

- Relapse in 12-week arm

• No RBV (n=7), RBV (n=4)

● Resistance

- No S282T variant at baseline or at time of virologic failure

- NS5A RAVs at baseline (n=62)

• Achieved SVR12: 89%


- Fatigue, nausea, insomnia, irritability, rash, dry skin, dyspnea, and anemia

NoRBV

(n=109)RBV

(n=111)

NoRBV

(n=109)

NoRBV

(n=111)


20

30

90

70

Death (number) 0 0 0 0


5

00

14

20

8

00

24

82


12 Weeks 24 Weeks


37

COSMOS Subgroup Analysis:Genotype 1 Prior Null Responders (F0-F2)

Simeprevir + Sofosbuvir qd (n=14)

Simeprevir + Sofosbuvir qd+ RBV (n=27)

Phase 2aOpen-labelGenotype 1Prior PR null responderNon-cirrhotic (F0-F2)

Week 0 12 24


Simeprevir + Sofosbuvir qd + RBV (n=24)

Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor); simeprevir 150 mg (NS3/4A Inhibitor).Weight-based ribavirin dosing (1000-1200 mg).Baseline demographics and disease characteristics: Male: 61%; age: 56 years; black: 29%. Genotype 1a: 78%. Genotype 1a with Q80K: 39%. IL28B non-CC: 94%. METAVIR F2: 59%. HCV RNA (log10 IU/mL): 6.8.

Sulkowski MS, et al. J Hepatol. 2014;60(suppl 1):S4. Abstract O7.

38

COSMOS Subgroup Analysis: SVR12 inGenotype 1 Prior Null Responders (F0-F2)

SV

R12

(%

)

SVR12

93%

24 Weeks(n=15/24)

12 Weeks(n=14/27)

Simeprevir + sofosbuvir No RBV With RBV

96%93%

79%

SV

R12

(%

)

SVR12 by Subgroups

100%

Genotype(n=17/30/27)

1b

100%

89%

Simeprevir + sofosbuvir + RBV


100% 100%

83%

1a 1a +Q80K IL28B Genotype

(n=4/52/18)

CC CT TT

39

COSMOS Subgroup Analysis:Genotype 1 Prior Null Responders (F0-F2)


- No virologic breakthroughs

- Relapse (n=3)

• 12-week arm (n=2, with and without RBV)

• 24-week arm (n=1 with RBV)

• All with Q80K at baseline

• Achieved undetectable HCV RNA at week 4

• No sofosbuvir RAVs at time of virologic failure

- Non-virologic (n=5)

• Due to adverse event (n=1), withdrew consent (n=1), noncompliance (n=1), lost to follow-up (n=1), non-treatment related death (n=1)


40

ABT-450/r/Ombitasvir + Dasabuvir + RBV in Treatment-Experienced Patients

● SAPPHIRE-II

- Previous PR failures

41

SAPPHIRE-II: ABT-450/r/Ombitasvir + Dasabuvir + RBV in Treatment-Experienced, HCV Genotype 1

Zeuzem S, et al. N Engl J Med. 2014;370:1604-1616.

3D + RBV(n=297)

Phase 3Double-blindGenotype 1Prior relapse, partial response, and null response to PRNon-cirrhoticHCV RNA >10K IU/mL18-70 years of age Week 0 12 24

3D: ABT-450 (NS3/4A inhibitor)/r/ombitasvir (NS5A inhibitor) 150/100/25 mg qd; dasabuvir (non-nucleoside NS5B polymerase inhibitor) 250 mg bid. RBV (1000-1200 mg). PR: pegIFN + RBV.Primary endpoint: SVR12 versus historical control SVR rate: 65% (telaprevir + pegIFN + RBV).Baseline demographics and disease characteristics: Male: 58% to 59%; age: 54-56 years; black: 9%-11%. Genotype 1a: 67%-68%. IL28B non-CC: 89%-93%. HCV RNA (log10 IU/mL): 6.5-6.6. Fibrosis stage F0-F1: 68%. Prior PR response: Relapse: 29%. Partial response: 22%. Null response: 49%.

Placebo(n=97)

3D + RBV

42

SAPPHIRE-II: SVR12 Rates With 3D + RBVin Treatment-Experienced, HCV Genotype 1

● Non-inferiority and superiority criteria met for overall SVR12 and superiority criteria met for SVR rate for genotype 1a and 1b

● SVR12 rates were similar across prior PR response subgroups

- Relapse (95%), partial response (100%), null response (95%)



- Relapse (n=7)

• Prior relapser (n=1), prior null responder (n=6)

- >1 RAV at time of virologic failure (n=5)

*

SV

R12

(%

)

96% 97%

Overall(n=297)

1a(n=173)

HCV Subtype

1b(n=123)

96%

SVR12Non-inferioritythreshold


PR: pegIFN + RBV.


43

SAPPHIRE-II: Safety of 3D + RBV inTreatment-Experienced, HCV Genotype 1

● Pruritus was more common in the 3D + RBV arm versus placebo (P<0.05)

● Serious adverse events possibly related to 3D + RBV (n=1)

- Transient ischemic attack in patients with hypertension, older age, atrial septal defect with shunt

● RBV dose modification due to adverse events (6.4%)

3D + RBV(n=297)


2.11.0

Death (number) 0

Laboratory abnormalities (%) ALT >5x ULN AST >5x ULN Alkaline phosphatase >5x ULN Total bilirubin >3x ULN Hemoglobin <10-8.0 g/dL <8.0 g/dL

1.71.00

2.4

4.70.3

Safety Summary


44

Program Overview







45

Retreatment for Prior DAA Failures

● Sofosbuvir + RBV or PR

- Prior sofosbuvir + RBV failures


- Prior sofosbuvir + RBV relapsers

● Sofosbuvir + PR

- Prior failures of PR + either GS-9451 or GS-9256 + ledipasvir or tegobuvir

46

Retreatment With Sofosbuvir-Based Regimens for Prior Sofosbuvir + RBV Failures (Interim Analysis)

Esteban R, et al. J Hepatol. 2014;60(suppl 1):S4-S5. Abstract O8.

Sofosbuvir qd + PR(n=34)

Open-LabelPrior relapsers of 12- or 16-weeks sofosbuvir + RBV in phase 3 studies (FISSION, FUSION, POSITRON) Genotype 2 or 3Compensated cirrhosis allowed

Week 0 12 24

Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor) + RBV (1000-1200 mg) + pegIFN.PR: pegIFN + RBV.Primary endpoint: SVR12.Baseline demographics and disease characteristics: Male: 77%-86%; age: 53 years; black: 1%. IL28B non-CC: 63%-68%. Mean ALT: 89-96 U/L. HCV RNA: 6.3-6.6 log10 IU/mL. Genotype 2/3: Sofosbuvir + PR: 18%/82%. Sofosbuvir + RBV: 7%/93%. Cirrhosis: Sofosbuvir + PR: 41%. Sofosbuvir + RBV: 34%.

Sofosbuvir qd + RBV(n=73)

47

SVR12: Retreatment With Sofosbuvir-Based Regimens for Prior Sofosbuvir + RBV Failures (Interim Analysis)


SV

R12

(%

)

100%

91%

50%

63%

Overall SVR12(Observed)

12-Week ArmSofosbuvir + PR

(n=4/22)

PR: pegIFN + RBV.

Genotype 2Genotype 3

24-Week ArmSofosbuvir + RBV

(n=2/38)

SV

R12

(%

)

93%88%

74%

47%

Genotype 3: SVR12(Observed)

12-Week ArmSofosbuvir + PR

(n=14/8)

No cirrhosisCirrhosis

24-Week ArmSofosbuvir + RBV

(n=23/15)

48

Safety: Retreatment With Sofosbuvir-Based Regimens for Prior Sofosbuvir + RBV Failures

● No deaths or discontinuations due to adverse events

- Grade 3/4 adverse events (sofosbuvir + PR versus sofosbuvir + RBV): 6% versus 1%

● Common adverse events

- Fatigue, headache, insomnia, irritability, depression, arthralgia, dry skin, pruritus, nausea

● Laboratory abnormalities (sofosbuvir + PR versus sofosbuvir + RBV)

- Grade 3/4: 38% versus 16%

- Hemoglobin <10 g/dL: 15% versus 0%

- Neutrophils <750/mm3: 9% versus 0%

- Platelets <50,000/mm3: 9% versus 0%


49

NIAID SPARE Study: Sofosbuvir/Ledipasvir Retreatment of Prior Sofosbuvir + RBV Relapsers

● Pilot study in genotype 1 (n=17)*

- Sofosbuvir + RBV relapsers from the NIAID SPARE

● Retreatment regimen (n=14)

- Sofosbuvir/ledipasvir (400/90 mg qd) for 12 weeks

● Primary endpoint: SVR12 (ITT analysis)

● Detection of S282T mutation during prior therapy with sofosbuvir + RBV

- End of treatment: 0%

- Week 28 post-treatment: 7% (1/14), reverted to wild type by week 36

Osinusi A, et al. J Hepatol. 2014;60(suppl 1):S5-S6. Abstract O11.

*3 patients did not participate: developed HCC (n=1), opted for telaprevir-based therapy (n=1), declined participation (n=1).Population sequencing (Sanger methodology) was performed for presence of NS5B mutations (sensitivity cut-off: 20%-25%).

Patients(n=14)

Male (%) 93

Age (years) 59.5

Black (%) 93

HCV genotype 1a (%) 57

IL28B non-CC (%) 86

HCV RNA log10 IU/mL 6.45

HAI stage 3-4 fibrosis (%) 50

Baseline Characteristics

50

NIAID SPARE Study: Sofosbuvir/Ledipasvir Retreatment of Prior Sofosbuvir + RBV Relapsers

● SVR12 (n=14): 100%

● Sofosbuvir/ledipasvir retreatment was well tolerated

- No deaths

- No grade 3/4 adverse events

- No discontinuations due to adverse events

● Grade 3 laboratory abnormalities

- Hypophosphatemia (n=2), hypercholesterolemia (n=1), elevated creatinine (n=1)

● Retreatment with sofosbuvir/ledipasvir

- No significant hemoglobin decline from baseline

- Mean 12-week hemoglobin decline versus previous sofosbuvir + RBV (-0.3 versus -1.2 g/dL; P<0.05)

- No changes in serum creatinine and estimated GFROsinusi A, et al. J Hepatol. 2014;60(suppl 1):S5-S6. Abstract O11.

51

Retreatment With Sofosbuvir-Based Regimens for Prior DAA + PR Failures (Interim Analysis)

● Single-arm study in HCV genotype 1 (n=80)

- Prior PR + DAA failures

• Either GS-9451 or GS-9256 and ledipasvir or tegobuvir

● Retreatment with sofosbuvir (400 mg qd) + PR for 12 weeks

● Primary endpoint: SVR12

- Available data (n=50)

- Characterized by NS3, NS5A, and NS5B exposure and RAVs prior to retreatment

Pol S, et al. J Hepatol. 2014;60(suppl 1):S23. Abstract O55.

Patients(n=80)

Male (%) 75

Age (years) 55

HCV genotype 1a (%) 85

IL28B non-CC (%) 84

HCV RNA log10 IU/mL 6.6

Duration of prior therapy (weeks) 25

>2 courses of therapy (%) 45

Number of prior DAAs (%) 1/2/3 19/51/30

Prior relapse (%) 48

Prior on-treatment failure (%) 45


52

SVR12: Retreatment With Sofosbuvir-Based Regimensfor Prior DAA + PR Failures (Interim Analysis)


SV

R12

(%

)

74%

SVR12

50%

75%

93%

Overall(n=50)

NS3(n=12)

NS3NS5a(n=24)

NS3NS5aNS5b(n=14)

Prior DAA + PR

SV

R12

(%

)

25%

SVR12 by Number of RAVs

73%80% 80%

0(n=4)

1(n=11)

2(n=25)

3(n=10)

Number Baseline RAVs Prior to Retreatment With Sofosbuvir + PR

53

Safety: Retreatment With Sofosbuvir-Based Regimens for Prior DAA + PR Failures

● No deaths or discontinuations due to adverse events

● Most common adverse events

- Fatigue (43%), headache (34%), nausea (24%), neutropenia (23%), rash (15%), myalgia (15%), dizziness (13%), pruritus (13%), anemia (13%), insomnia (10%), cough (10%)

● Grade 3/4 adverse events (10%)

● Laboratory abnormalities

- Grade 3/4: 51%

- Hemoglobin <10 g/dL: 8%

- Neutrophils <750/mm3: 21%

- Platelets <50,000/mm3: 0%


54

Program Overview







55

Sofosbuvir-Based Studies in Difficult-to-Cure and Liver Transplant Patients


- ELECTRON-2

● Sofosbuvir + RBV or PR

- Cirrhosis and portal hypertension + decompensation

- Multiple negative predictors

- Post liver transplantation

● Sofosbuvir + simeprevir

- COSMOS (F3-F4)

56

Sofosbuvir/Ledipasvir in Difficult-to-Cure Populations: ELECTRON-2 Study

Gane EJ, et al. J Hepatol. 2014;60(suppl 1):S3-S4. Abstract O6.

Sofosbuvir/Ledipasvir qd + RBV (n=26)


Demographics

Male: 68%, age: 55 yearsWhite: 95%Genotype 1a: 89%Cirrhosis: 0%IL28B CC: 21%HCV RNA: 6.3 log10 IU/mL

12-Week Treatment


Genotype 1(Prior relapse with sofosbuvir [ELECTRON-1])

SOF + RBV: null responders (n=6); naïve (n=4)SOF/LDV + RBV: naïve (n=6)SOF + GS-9669 + RBV: naïve (n=1)


Genotype 1Decompensated Cirrhosis (CTP class B)

Total bilirubin 1.5 mg/dL; serum albumin 3.1 g/dL;INR 1.2; ascites 20%; hepatic encephalopathy (30%); platelets 84,000/mm3

Demographics

Male: 85%, age: 56 yearsWhite: 85%Genotype 1a: 90%Cirrhosis: 100%IL28B CC: 35%HCV RNA: 6.0 log10 IU/mL

Genotype 3Treatment-NaïveDemographics

Male: 42%-52%, age: 43-48 yearsWhite: 88%Genotype 3a: 100%Cirrhosis: 12%-19%IL28B CC: 36%-58%HCV RNA: 6.3 log10 IU/mL

SVR12Hemoglobin

<10 g/dL

100% 16%

65% 5%

100% 12%

64% 0%

57

Sofosbuvir-Based Regimens Across Genotypes and Multiple Negative Predictors

Foster GR, et al. J Hepatol. 2014;60(suppl 1):S27. Abstract O66.

Retrospective analysis of predictors of relapse associated with sofosbuvir-based regimens and calculated SVR rates by number of negative predictors (prior treatment, male gender, body weight >75 kg, IL28B non-CC genotype, cirrhosis, baseline HCV RNA >800K IU/mL).

SV

R12

(%

)

100%100% 100%99% 100%

93%96%

100%100% 100%

93%

86%

94%

86%

61%

79%

62%

67%

53%

3(n=122/81/59)

0(n=0/4/5)

Number of Negative Predictors

1(n=26/22/22)

2(n=69/70/43)

6(n=0/6/15)

4(n=104/69/66)

5(n=18/33/37)

N/AN/A

Genotype 1 (ATOMIC, NEUTRINO) Genotype 2 (FISSION, POSITRON, FUSION, VALENCE) Genotype 3 (VALENCE)

58

Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + Decompensation

Afdhal N, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.

Sofosbuvir qd + RBV(n=25)

Observation(n=25)

Open-LabelGenotypes 1-4Treatment-naïve and experiencedCompensated cirrhosis (Child-Pugh 5-6, A)Decompensated cirrhosis (Child-Pugh 7-9, B)Esophageal or gastric varicesHepatic venous gradient (HVPG): >6 mm Hg)

Week 0 24 48 72

Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor) + RBV (1000-1200 mg).HVPG at day 0 and 48 in the sofosbuvir-treated patients.Baseline demographics and disease characteristics: Male: 72%-80%; age: 55-56 years; white: 84%-96%, treatment-naive: 68%-92% . Genotype 1a, 1b, 2, 3, 4: 36%-40%, 24%-36%, 4%-8%, 8%-32%, 4%-8%. IL28B non-CC: 72%-88%. HVPG >12 mm Hg: 76%-80%. CTP score 5-6, 7-9: 36%-44%, 56%-60%. MELD <10, 10-15: 32%, 56%-60%. Albumin: 3.0-3.3 g/dL; platelets: 75-99 x103. ALT, AST: 87-105, 105-128 U/mL. Ascites: 24%-36%. Encephalopathy 8%-20%.

Sofosbuvir qd + RBV

Current Analysis

59

Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + Decompensation

● High rates of virologic suppression irrespective of severity of liver disease

● Decreased necroinflammation with ALT normalization

● Improvements

- Platelet count and albumin

- Ascites and hepatic encephalopathy

● Low rates of treatment discontinuation due to adverse events (4%)

Afdhal N, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.

Sofosbuvir+ RBV(n=25)

Observation(n=25)

HCV RNA <LLOQ (%) CTP A (n=7) CTP B (n=15)

10090

----

Change Platelets (103/µL) CTP A CTP B Albumin (g/dL) CTP A CTP B Bilirubin (mg/dL) CTP A CTP B ALT (U/L) CTP A CTP B

171

0.50.4

0.5-0.2

-72-75

-9-1

-0.10

0.2-0.1

130

Outcomes at Week 24

60

Sofosbuvir Compassionate Use Program:Recurrent HCV Following Liver Transplantation

● Patients with severe recurrent HCV infection following liver transplantation

- Likely to have <1 year life expectancy

● Sofosbuvir 400 mg qd + RBV + pegIFN for up to 48 weeks

● Recommended time of clinical assessments

- On treatment: weeks 4, 12, 24, 36, and 48

- Follow-up: weeks 4, 12, and 24

Patients(n=104)

Male (%) 73

Age (years) 55

Genotype (%) 1a/1b 2/3/4

28/491/7/8/

ALT (IU/L) 71

Bilirubin (mg/dL) 3.1

Albumin (g/dL) 3.1

INR 1.3

MELD score 15

Time from liver transplantation (months)

17


PR: pegIFN + RBV.

Forns X, et al. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.

61

Sofosbuvir Compassionate Use Program:Initial Treatment Evaluations

● Overall, liver function tests significantly improved over time

● Most patients improved clinically or remained stable

● All serious adverse events (48%)

- Leading to treatment discontinuation (13%)

● Deaths (13%) were mostly a result of disease progression in this very sick population

- On treatment (n=8)

- Post treatment follow-up (n=5)

Pat

ien

ts (

%)

Treatment Outcomes

62% 62%

21%

SVR12(n=85)

Improved* Stable

*Improved: improvement in decompensation events (ie, significant decrease in hepatitic encephalopathy episodes, improvement or disappearance of ascites, and improvement in liver-related laboratory values.

Forns X, et al. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.

Worse

Clinical Outcomes(n=104)

21%

62

Sofosbuvir + RBV: Treatment ofRecurrent HCV After Liver Transplantation

● Open-label study

- Genotype 1(83%), 3 (15%), 4 (3%)

- Prior HCV treatment (88%)

- CTP <7 and MELD <17

- Time liver transplantation: 4.3 years

- METAVIR F3/F4: 23%/40%

● Sofosbuvir 400 mg qd + RBV (starting at 400 mg) for up to 24 weeks

● Primary efficacy endpoint: SVR12

● Safety

- No deaths, graft losses, or rejection

- Discontinuations due adverse events: 5%

- RBV dose escalation manageable

- No interactions with common immunosuppressant agents

Patients

(n=40)

HCV RNA <25 IU/mL (%) Week 4 SVR4 SVR12 SVR24

100737070

Concomitant immunosuppression (%) Tacrolimus Mycophenolate mofetil Prednisone Cyclosporin Azathioprine

703528255

Adverse events (%) Fatigue Headache Arthralgia

282523

Grade 3/4 laboratory abnormalities (%) 25/28

Key Results

Samuel D, et al. J Hepatol. 2014;60(suppl 1):S499. Abstract P1232.

63

COSMOS Subgroup Analysis:HCV Genotype 1, METAVIR F3-F4


Simeprevir + Sofosbuvir qd+ RBV (n=27)

Phase 2aOpen-labelGenotype 1Prior PR null responder or treatment-naïve METAVIR F3-F4No BMI limit<70 years of age

Week 0 12 24


Simeprevir + Sofosbuvir qd + RBV (n=30)

Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor); simeprevir 150 mg (NS3/4A Inhibitor).Weight-based ribavirin dosing (1000-1200 mg).Baseline demographics and disease characteristics: Male: 67%; age: 58 years; black: 9%. Genotype 1a: 78%. Genotype 1a with Q80K: 40%. IL28B non-CC: 79%. Cirrhosis: 47%. HCV RNA (log10 IU/mL): 6.6. Prior PR null responders: 54%.

Lawitz E, et al. J Hepatol. 2014;60(suppl 1):S524. Abstract O165.

64

COSMOS Subgroup Analysis:SVR12 in HCV Genotype 1, METAVIR F3-F4

SV

R12

(%

)

SVR12

93%

24 Weeks(n=16/30)

12 Weeks(n=14/27)

Simeprevir + sofosbuvir No RBV With RBV

93%100%

93%

SV

R12

(%

)


100%

Genotype(n=18/40/26)

1b

95% 96%

Simeprevir + sofosbuvir + RBV

94%98%

95%

1a 1a +Q80K IL28B Genotype

(n=17/48/19)

CC CT TT

Lawitz E, et al. J Hepatol. 2014;60(suppl 1):S524. Abstract O165.

65

COSMOS Subgroup Analysis:HCV Genotype 1, METAVIR F3-F4

● SVR12 rates were similar regardless of prior treatment exposure or baseline METAVIR score

● Relapse (n=3)

- All were genotype 1a, undetectable at EOT, and in 12-week arm (n=2 with RBV)

- At time of relapse there were no sofosbuvir RAVs

• Simeprevir RAVs: D166E, R155K

● Sofosbuvir + simeprevir + RBV was safe and well tolerated

- Discontinuations due to adverse events (1.1%)

- Higher incidence of adverse events and laboratory abnormalities in the RBV-containing arms

- Most common adverse events

• Fatigue (38%), headache (20%), nausea (17%), anemia (13%), pruritus (13%)

- Grade 3/4 laboratory abnormalities

• Hyperbilirubinemia (8%)

• Hemoglobin (1%) Lawitz E, et al. J Hepatol. 2014;60(suppl 1):S524. Abstract O165.

66

ABT-450/r/Ombitasvir + Dasabuvir + RBV

● TURQUOISE-II

- Compensated cirrhotics (genotype 1)

67

TURQUOISE-II: ABT-450/r/ABT-267 +ABT-333 + RBV in Compensated Cirrhotics

Poordad F, et al. N Engl J Med. 2014;April 11. [Epub ahead of print].

3D + RBV(n=208)

Phase 3Open-labelGenotype 1Treatment-naïve and PR experienced Child-Pugh APlatelets: >60K/mLSerum albumin: >2.8 g/dLTotal bilirubin: <3 g/dLINR: <2.3AFP: <100 ng/mL Week 0 12 24

3D: ABT-450 (NS3/4A inhibitor)/r/ombitasvir (NS5A inhibitor) 150/100/25 mg qd; dasabuvir (non-nucleoside NS5B polymerase inhibitor) 250 mg bid. RBV (1000-1200 mg). PR: pegIFN + RBV.Primary endpoint: SVR12 versus historical control SVR rate: 43% and 54% for non-inferiority and superiority, respectively (telaprevir + pegIFN + RBV).Baseline demographics and disease characteristics: Male: 70%; age: 57 years; black: 4%-6%. Genotype 1a: 67%-70%. IL28B non-CC: 80%-83%. Treatment naïve: 41%-43%. Prior PR response: Relapse: 13%-14%. Partial response: 8%-9%. Null response: 36%.Child-Pugh score >5: 18%-19%.

3D + RBV(n=172)

68

TURQUOISE-II:SVR12 in Compensated Cirrhotics

SV

R12

(%

)

92%96%

SVR12

12-Week Arm(n=208)

24-Week Arm(n=172)

3D + RBV

SV

R12

(%

)

89%

98%94%

100%


1a 1bNon-inferioritythreshold


12-Week Arm(n=140/68)

24-Week Arm(n=121/51)

3D + RBV


69

TURQUOISE-II:SVR12 by Prior Treatment Response

SV

R12

(%

)

92%

100%

12-Week Arm

1a 1b

Naive(n=64/22)

Relapse(n=15/25)

Prior PR Response

Partial(n=11/7)

Null(n=50/14)

93%

100% 100%

86%80%

100%

SV

R12

(%

)

93%100%

24-Week Arm

1a 1b

Naive(n=56/18)

Relapse(n=13/20)

Prior PR Response

Partial(n=10/3)

Null(n=42/10)

100%100% 100%100%93%

100%

PR: pegIFN + RBV.


70

TURQUOISE-II: SVR12 by Baseline Surrogates of Portal Hypertension and Hepatic Function

SV

R12

(%

)

89%

12-Week Arm

<100(n=45)

>100(n=163)

Platelets(x109/L)

<35(n=25)

>35(n=183)

93%84%

93%

24-Week Arm

PR: pegIFN + RBV.

Serum Albumin(g/L)

SV

R12

(%

)

97%

<100(n=45)

>100(n=163)

Platelets(x109/L)

<35(n=25)

>35(n=183)

96%89%

97%

Serum Albumin(g/L)


71

TURQUOISE-II: Safety of 3D + RBVin Compensated Cirrhotics

● Virologic failure (4.5%)

- >1 RAVs at time of virologic

failure (n=15)

● Hepatic decompensation (1.1%)

● Anemia managed with RBV dose reduction

- No impact on achieving SVR12

● Common adverse events

- Fatigue, headache, nausea, pruritus, insomnia, diarrhea, asthenia, rash, cough, irritability, anemia, dyspnea

12 Weeks(n=208)

24 Weeks(n=172)

Virologic failure (%) Breakthrough Relapse

0.55.9

1.70.6


131.9

122.3

Death (number) 0 0

Laboratory abnormalities (%) ALT >5x ULN Total bilirubin >3x ULN Hemoglobin <10 g/dL <8.0 g/dL

2.913.5

7.21.4

05.2

11.00.6

Virologic Failure and Safety Summary


72

Program Overview







73

NIAID ERADICATE Study: Sofosbuvir/Ledipasvir in HCV Genotype 1 With HIV Coinfection (Interim Analysis)

Osinusi A, et al. J Hepatol. 2014;60(suppl 1):S7. Abstract O14.

Sofosbuvir/Ledipasvir (n=13)SVR12 (interim analysis)

Open-LabelHCV genotype 1HCV treatment-naïveHAI fibrosis stage 0-3ART-naïve: HIV RNA <40 copies/mL and CD4 stable or CD4 >500 cells/mm3

On ART: CD4 >100 cells/mm3 HIV RNA <40 copies/mL Current ART >8 weeks

Week 0 12 24

Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor)/ledipasvir 90 mg (NS5A inhibitor).Primary endpoint: SVR12.Allowable ART: emtricitabine/tenofovir DF (100%) plus: efavirenz (41%), raltegravir (27%,), rilpivirine (21%), rilpivirine/raltegravir (8%), efavirenz/raltegravir (3%).Baseline demographics and disease characteristics: Male: 54%-81%; age: 58 years; black: 77%-86%. Genotype 1a: 75%-81%. HAI fibrosis stage 3: 22%-38%. HCV RNA (log10 IU/mL): 5.97-6.07. CD4 cells/mm3: ART-naïve: 687. On ART: 576.

Sofosbuvir/Ledipasvir (n=13)SVR4 (interim analysis)

ART-Naïve

On ART

74

NIAID ERADICATE Study: Sofosbuvir/Ledipasvir in HCV Genotype 1 With HIV Coinfection (Interim Analysis)

● No change within groups

- CD4 counts or CD4 T-cell percentages

- Serum creatinine or estimated GFR

● HIV RNA status during HCV treatment

- ART-naïve: no clinically significant change

- On ART: transient HIV RNA breakthrough (missed ART for 4 days), re-suppressed

- No change within groups

● Sofosbuvir/ledipasvir was well tolerated

- No deaths, grade 4 adverse events or discontinuations due to adverse events

- Laboratory abnormalities

• Grade 3: neutropenia (n=1), AST (n=1)

• Grade 4: creatinine phosphatase (n=1)

Osinusi A, et al. J Hepatol. 2014;60(suppl 1):S7. Abstract O14.

SV

R (

%)

100% 100% 100%

Not YetAvailable

SVR Rates(Interim, Observed)

ART-Naïve(n=12/10)

SVR4SVR12

On ART(n=22/0)

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Post Conference HCV Update 49 th Annual Meeting of the European Association for the Study of the...

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